The Cardiac Syndrome X, signs and symptoms of myocardial ischemia without epicardial coronary artery disease (CAD), can be associated with a stress-induced reduction in the myocardial phosphocreatine-adenosine triphosphate ratio, as measured by phosphorous-31 nuclear magnetic resonance spectroscopy (MRS). Johnson and colleagues, from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE) study, sought to determine the prognostic value of an abnormal MRS, indicative of myocardial ischemia, in the absence of CAD. Women, referred for coronary angiography for suspected myocardial ischemia, underwent handgrip stress MRS and follow-up evaluation.

There were 3 groups: 1) 60 with no CAD and a normal
stress MRS; 2) 14 with no CAD and an abnormal MRS;
3) 352 with CAD, 13 of whom had MRS. The primary
end point was freedom from cardiovascular events—death, myocardial infarction, heart failure, stroke, and hospitalization for unstable angina. Compared to those with CAD, those without were younger, had fewer CAD risk factors, and had a higher frequency of hormone therapy. Women with an abnormal MRS were likely to be
smokers. Cumulative freedom from cardiovascular
events at 3 years was 87, 57, and 52% for groups 1-3,
respectively (P < .01). Among the 74 without CAD,
most of the events were hospital admissions for unstable
angina. After adjustment for confounders, an abnormal
MRS was an independent predictor of events (P = .02). Total costs were highest for CAD patients, but for the no CAD abnormal MRS women, the costs were similar to the CAD women ($11,102 vs $14,495; P = NS). Johnson et al concluded that an abnormal stress MRS, indicative of myocardial ischemia in symptomatic women without CAD, predicts cardiovascular events, especially hospitalization for unstable angina.

Comment by Michael H. Crawford, MD

The results of this study suggest that a subgroup of
women without CAD have symptoms caused by
myocardial ischemia that can be detected by stress MRS.
Johnson et al’s experience suggests that this subgroup
represents 20% of such women. Of importance, this
study shows that they have almost the same number of
cardiovascular events over 3 years as women with CAD.

Presumably, this disorder, sometimes called Syndrome X, is due to microvascular disease. Unfortunately, as this study confirms, the usual therapy for myocardial ischemia is not particularly effective. Thus, these women are frequently hospitalized, and undergo invasive and noninvasive tests, which increase health care costs.

The implication of this study is that by using handgrip stress MRS, these women can be identified and appropriately managed, reducing health care costs. Johnson et al claim that other tests for myocardial ischemia in these women have shown inconsistent results, and therefore, are not as good as MRS. However, this remains to be proven, and there are several limitations to MRS. First, MRS only samples the anterior myocardium. So whether the MRS test is positive or negative for ischemia, you still cannot rule out CAD, nor that the microvascular disease is localized. Thus, all patients suspected of having
Syndrome X require cardiac catheterization. Second,
handgrip stress may not be sufficient to bring out myocardial ischemia, but this is the only type of exercise feasible in these small bore magnets. Perhaps dobutamine or other pharmacologic agents would increase the sensitivity for detecting myocardial ischemia. Finally, this is a small study that was underpowered to detect hard events. There were no deaths or MIs
over the 3 years. At this point, the value of this article is that it
substantiates, by sophisticated metabolic analysis, that this syndrome exists
and represents a challenge to physicians who care for patients with chest pain.

Dr. Crawford, Professor of Medicine, Chief of Clinical Cardiology
University of California
San Francisco, is Editor of Clinical Cardiology Alert.

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